Foreign epitope–specific regulatory T cells respond robustly to vaccination and limit Th1 differentiation by conventional T cells specific for the same epitope

Foxp3+ regulatory T (Treg) cells with antigen receptors (TCRs) specific for host peptides suppress autoimmunity. Paradoxically, Treg cells are also found in CD4+ T-cell populations specific for foreign (nonhost) peptides. We investigated the origin and function of these Treg cells in mice. Populations of foreign peptide-specific naïve CD4+ T cells contained Foxp3- conventional (Tconv) and Foxp3+ Treg cells in about a 90:10 ratio. Both types of T cells proliferated in parallel after vaccination with the foreign peptide in incomplete or complete Fruend's adjuvants and formed memory cells. The Tconv population failed to express Foxp3, and formed Th1, Th17, and T follicular helper cells, whereas the Treg population largely retained Foxp3, and formed Th1- and Th17-like cells. The Treg cells specific for a foreign peptide had no effect on the proliferation of Tconv cells specific for that peptide but partially reduced Th1 cells in that population. Thus, foreign epitope-specific naïve Treg cells fine-tune the primary response of Tconv cells specific for the same epitope by curbing the Th1 fate while allowing a robust response.